7 CARBONYL COMPOUNDS ENOLS AND ENOLATE ONS. UNSATURATED AND POLYCARBONYL COMPOUNDS ome of the most useful reactions of carbonyl compounds involve carbon- hydrogen bonds adjacent to the carbonyl group. Such reactions, which can be regarded as the backbone of much synthetic organic chemistry, usually result in the replacement of the hydrogen by some other atom or group, as in the I I I I sequence H-C-C=O -+ X-C-C=O. The important examples we I I will consider in this chapter are halogenation, alkylation, and aldol reactions of aldehydes and ketones, illustrated here for 2-propanone: Br halogenation 0 CH,I I/ C C /CH3 alkylation cH/, \CH, ' cH/, \CH, I aldolization 736 17 Carbonyl Compounds II. Enols; Enolate Anions. Unsaturated and Polycarbonyl Compounds Although these reactions lead to many diverse products depending on the reagents and conditions, they have one feature in common- they proceed by way of the en01 or the enolate anion of the parent carbonyl compound: carbonyl form enolate anion enol form Therefore, to understand the nature of these reactions we first must under- stand the conditions that convert aldehydes and ketones to their en01 forms or the anions of those en01 forms. 17-1 ENOLIZATION OF ALDEHYDES AND KETONES Transformation of a carbonyl compound to an en01 at a useful rate normally requires either a basic catalyst or an acidic catalyst and, of course, at least one hydrogen on the a carbon. The features of each type of catalysis follow. 17-1A Enolization in Basic Solution. C-H Acidity of Carbonyl Compounds With a basic catalyst such as hydroxide ion, the first step in enolization is removal of a proton from the a position to give the enolate anion 1: Normally, C-H bonds are highly resistant to attack by basic reagents, but re- moval of a proton alpha to a carbonyl group results in the formation of a con- siderably stabilized anion with a substantial proportion of the negative charge on oxygen, as represented by the valence-bond structure la. Carbonyl com- pounds such as 2-propanone therefore are weak acids, only slightly weaker than alcohols (compare the pK, values for some representative compounds in Table 17- 1).l lThe important difference between 2-propanone and ethanol as acids is that the rate of establishment of equilibrium with 2-propanone or similar compounds where ioniza- tion involves breaking a C-H bond is very much slower than the corresponding reac- tion with 0-H bonds. 17-1 Enolization of Aldehydes and Ketones Table 17-1 C-H and 0-H Acidities of Some Representative Compoundsa C-H Acidity 0-H Acidity Compound PKa Compound PK.3 0 II RO-C-CH, 25 "These are approximate values; the acidic hydrogen is shown in boldface type; pKa is defined in Section 8-1. Two carbonyl groups greatly increase the acidity. For example, 2,4- pentanedione (acetylacetone, 2) has a pK, = 9, which is comparable to the 0-H acidity of phenols (see Table 17-1). The reason is that the enolate anion 3 has the charge largely shared by the two oxygen atoms (cf. 3b and 3c). As a result, the enolate anion 3 is stabilized more with respect to the 738 17 Carbonyl Compounds 11. Enols; Enolate Anions. Unsaturated and Polycarbonyl Compounds ketone than the enolate anion from 2-propanone is stabilized relative to 2-propanone: -0 -0 :o: :o: :o. :o: :o: :o. II I I I II I/ I C C C ,C\@ ,c\ - ,\ - CH, CH. CH, cH/, \CH CH, cH/, \~6\CH, Exercise 17-1 Other groups in addition to carbonyl groups enhance the acidities of adjacent C-H bonds. For instance, nitromethane, CH3N02,has pK, = 10; ethane- nitrile, CH3CN, has a pK, = 25. Explain why these compounds behave as weak acids. Why is CH3COCH, a stronger acid than CH3C02CH3? Exercise 17-2 Draw valence-bond structures to represent the anions derived from the following compounds in the presence of a strong base. Assume that the base functions to remove the most acidic proton. 17-1B Enol Formation from Enolate Anions You will notice from Structures la and I b that because the negative charge of the enolate anion is distributed on both oxygen and carbon, the ion can, in principle, combine with a proton at either site. If the enolate ion adds a proton to oxygen, the en01 is formed; if it adds a proton to carbon, the ketone is formed: en01 ketone 17-1C Enolization in Acid Solution 739 Ions of this type, which can react at either of two different sites, often are called ambident ions. In fact, enolate anions add a proton at oxygen at least 1010 times faster than at carbon; the proton also is removed from oxygen much faster than from carbon. Thus the enolate anion of 2-propanone is in rapid equilibrium with the enol, but is converted back and forth to the ketone only slowly (Equation 17-1). Another important point is that, although enolization by way of enolate anions requires a basic catalyst, both an acid and a base are necessary: a base to form the enolate anion; an acid to donate a proton to the anion to form the enol. If there is no acid available that is strong enough to donate a proton to the anion, then only the enolate anion is formed: O O OH I/ base 1; 0 acid I R-C-CH, R-C=CH ------+R-C=CH, 17-1C Enol ization in Acid Solution Catalysis of the enolization of 2-propanone by acids involves first, oxonium- salt formation and second, removal of an a proton with water or other proton acceptor (base): This sequence differs from enolization induced by basic catalysts (as discussed in Section 17-1B) in that the en01 is formed directly and not sub- sequent to the formation of the enolate anion. The proton addition to the carbonyl oxygen greatly facilitates proton removal from the a carbon because of the electron-attracting power of the positively charged oxygen. Neverthe- less, this last step is the rate-determining step for enolization in acid solution. bT&-X bT&-X 4-?&&iWWr&* A&--'L.Y-*&L* +CZmdrfl>L~A-VA*-LY* w~TA~*d"-ebZ$Z-2 .+&W&WmcW#2%@a2&w@?bb< ~~S%~F&*~&-~T~%~~~SW~W#WMWW Exercise 17-3 Explain why the D or L enantiomer of a chiral ketone such as 4-phenyl- 3-methyl-2-butanone racemizes in the presence of dilute acid or dilute base. 17 Carbonyl Compounds II. Enols; Enolate Anions. Unsaturated and Polycarbonyl Compounds Table 17-2 The Enol Content of Some Carbonyl Compounds Compound Percent enol (solvent) cyclopentanone, 00 cyclohexanone, 00 85 (none) 5,5-dimethylcyclohexane-1,3-dione, 95 (H2O) 2,4-cyclohexadienone, Q" -100 (keto form of phenol) H H 17-ID Stabilities of Enols The equilibrium position between a simple ketone and its en01 usually lies far on the side of the ketone (see Table 17-2). However, there are some interesting and important exceptions to this generalization. For instance, the influence of two carbonyl groups on the en01 content is very striking, as we can see from the fact that 85% of 2,4-pentanedione is the en01 form at equilibrium: 0 0 ..H\ I I I I 0' ' 0 C C d /\ /\ II I CH, CH, CH, c 4c\ c$, \CH CH, The en01 form of 2,4-pentanedione (and of related dicarbonyl compounds of the II I type 0 =C -CH-C= 0) not only is stabilized by electron-delocalization, 17-ID Stabilities of Enols 741 as shown in Structures 4a and 4b, but by hydrogen-bonding of the acidic hydrogen between the two oxygens: hyqrogen bonding Of course, such stabilization is not possible for the keto form. An extreme example of the stabilization of an en01 by electron de- localization is benzenol (phenol), which exists 100% in the en01 form. In this case the extra stability of the benzene ring is the important factor: In the succeeding sections of this chapter we will discuss several im- portant reactions that take place by way of enols or enolate anions. Exercise 17-4 a. The proton nmr spectrum of 2,4-pentanedione is shown in Figure 17-1, Interpret this spectrum by assigning each resonance to a structurally different proton, and explain why the broad resonance at 15 ppm is at unusually low field strengths. b. What does this spectrum indicate about the rates of the establishment of each of the following equilibria? Give your reasoning (review Sections 9-10E and 9-1 OC). 742 17 Carbonyl Compounds II. Enols; Enolate Anions. Unsaturated and Polycarbonyl Compounds Figure 17-1 Proton nmr spectrum of 2,4-pentanedione at 60 MHz. Cali- brations are relative to tetramethylsilane. 17-2 HALOGENATION OF ALDEHYDES AND KETONES 17-2A Synthesis of a-Halo Ketones Halogenation of saturated aldehydes and ketones usually occurs exclusively by replacement of hydrogens alpha to the carbonyl group: 0 0 II I/ CH3-C-CH3 + CI2 --+ CH3-C-CH2CI + HCI I-chloro-2-propanone (chloroacetone) The reagents that commonly are used to halogenate carbonyl com- pounds are those that are used to halogenate alkanes (e.g., Cl,, Br,, SO,Cl,, and N-bromoamides; see Sections 4-4 and 14-3). However, the characteris- tics of the two types of halogenation normally are very different. 2-Propanone has been particularly well studied, and the important features of the halogena- tion of this compound are summarized as follows: 1. 2-Propanone reacts easily with chlorine, bromine, and iodine. 17-2A Synthesis of @-HaloKetones 743 2.